Process for production of d, l-glutamic acid from alpha-ketoglutaric acid



Aug. 4, 1964 GENTARO NOYORI ETAL 3,143,565

PROCESS FOR PRODUCTION OF D,L-GLUTAMIC ACID Remaining amoum Yield of 0-kefog/ufaric acid d-kefoglutaric acid FROM ((-KETOGLUTARIC ACID FiledApril 19, 1962 Fig. l

Standing period of o! -kefoglu1aric acid so/ufion lnr.)

Fig. 2

Standing period of -kafog/ufaric acid solution lhr.)

INV EN TOR.

United States Patent Oflice 3,143,565 Patented Aug. 4, 1964 3,143,565PRC'CESS FOR PRGDUCTION F D,L-GLUTAMIC ACID FROM a-KETOGLUTARIC ACIDGentaro Noyori, Hidehiro Okazaki, Hidemoto Kurokawa, and Makoto Honda,all of Tokyo, Japan, assignors to The Noguchi Institute, Tokyo, Japan, acorporation of Japan Filed Apr. 19, 1962, Ser. No. 188,795 7 Claims.(Cl. 260-482) This invention relates to an improved method forproduction of D,L-glutamic acid from a-ketoglutaric acid. Moreparticularly, this invention relates to a process for providing aD,L-glutamic acid solution in nearly theoretical yield by aminativereduction of a-ketoglutaric acid, salts and/ or esters thereof in anammonia solution in the presence of hydrogenating catalyst or catalystsand in hydrogen atmosphere, wherein portions of the starting material ormaterials are introduced continuously into the reaction zone at such arate as to keep the concentration of the starting material or materialsas free acid base in the reaction mixture not to exceed 2% by weight,preferably in the range between 0.02 and 2% by weight.

a-Ketoglutaric acid, the starting material, is prepared from furfuralthrough the intermediate, 2,5-dialkoxy-2,5- dihydrofuroic acid or fromglucose by fermentation, and is now noted to be an important source ofglutamic acid.

In the conventional process of aminative reduction of a-ketoglutaricacid or salts thereof, they were dissolved in aqueous ammonia or aqueousammonia was added to a-ketoglutaric acid, followed by catalyticreduction to convert u-ketoglutaric acid into D,L-glutamic acid. Thecatalyst employed was palladium, platinum, reduced nickel or Raneynickel; and heating and superatmospheric pressure were applied in thereduction with the nickel catalyst. However, as Well known to the art,this process could not give the product in practically sufficient yield.

Although a variety of improvements such as increasing concentration ofammonia or equivalent ratio of ammonia to a-ketoglutaric acid have beenproposed, the difliculties in the conventional method have never beenovercome completely.

It is an object of the present invention to provide the improved methodfor converting a-ketoglutaric acid into D,L-glutamic acid in nearlytheoretical yield.

It is another object of the present invention to provide an improvedmethod for producing D,L-glutamic acid, comprising catalytic reductionof a-ketoglutaric acid, salts and/or esters thereof in aqueous andalcoholic ammonia solution in the presence of catalysts such aspalladium, platinum, reduced nickel, Raney nickel and the like inhydrogen atmosphere, wherein the starting materials are continuouslyintroduced in the reaction zone at such a rate as to keep theconcentration of the unchanged starting material calculated as free acidin the reaction mixture not to exceed 2% by weight, preferably in therange between 0.02 and 2% by weight.

FIG. 1 shows graphically a change of remaining amount of u-ketoglutaricacid initially dissolved to a concentration of 8% by Weight in 14%aqueous ammonia and allowed to stand at a temperature of 2025 C.; theamount of a-ketoglutaric acid is determined on the basis of2,4-dinitrophenylhydrazone precipitate obtained by adding a 0.01 Naqueous solution of 2,4-dinitrophenylhydrazine. Substantial same resultis obtained with an aqueous sodium hydroxide solution. It is seen fromthe graph that a-ketoglutaric acid or salts thereof are unstable in anaqueous ammonia solution.

FIG. 2 represents a change in amount of D,L-glutamic acid produced froma-ketoglutaric acid or salts thereof dissolved in the aqueous ammoniaand allowed to stand for a period of time prior to catalytichydrogenation.

Reference to both FIGURES 1 and 2 indicate that the yield ofD,L-glutamic acid depends upon standing period of time of a-ketoglutaricacid in an aqueous ammonia solution. From this result, we have foundthat a-ketoglutaric acid may be converted into D,Lglutamic acid innearly theoretical yield, when the former is continuously introducedinto aqueous ammonia solution at such a rate as to keep the startingmaterial of a-ketoglutaric acid or salts thereof, in the reactionmixture at the minimum concentration. That is, the efficient conversionof oc-klO- glutaric acid or salts thereof into D,L-glutamic acid can beeffected by subjecting the acid or salts thereof to the conversion assoon as they are introduced into the reaction mixture.

We have observed that the nearly theoretical yield of D,L-glutamic acidis obtained by introducing a-ketoglutaric acid or salts or estersthereof at such a rate as to keep the concentration of the unchangedstarting material calculated as free acid in the reaction mixture not toexceed 2%, preferably in the range between 0.02 and 2% by weight, in theprocess of aminative hydrogenating conversion of a-ketoglutaric acidinto D,L-glutamic acid in the presence of catalyst and in hydrogenatmosphere. This improvement is found to greatly contribute tocommercial production of glutamic acid, because concentrated glutamicacid solution can be obtained in approximately theoretical yield.

In the process of this invention, as described later in examples,palladium, platinum, Raney nickel, reduced nickel and the like may beemployed as the hydrogenating catalyst. a-Ketoglutaric acid, solublesalts thereof including sodium-, potassium-, ammonium salt ofa-ketoglutaric acid and the like and lower alkyl esters thereofincluding methyl-, ethyl-, propyl-, butyl ester of a-ketoglutaric acidand the like are useable as the starting material; water, methylalcohol, ethyl alcohol and C -C alcohols and the like added withammonia, as reaction medium.

The catalytic aminative hydrogenation reaction may be carried out at atemperature in the range between 10 C. and C. and in a hydrogenatmosphere at a pressure in the range between 1 and 200 kg./cm.

The embodiment of this invention will be described in greater detail inthe following specific examples.

Example 1 One hundred twenty-three grams of a-ketoglutaric acid (97.8%purity) was neutralized with an aqueous sodium hydroxide solution, madeup to 720 ml. with water and added with 780 ml. of 28% aqueous ammonia(NH 2l0 g.)

An aliquot of this solution (250 ml.), containing 20 g. (8%) ofa-ketoglutaric acid and 35 g. (14%) of ammonia in molar ratio of 1: 15,was employed for a single run of reaction.

In a 500 ml. autoclave, equipped with a vertical magnetic stirrer, wereplaced 250 ml. of the above prepared solution and 4-5 g. of Raneynickel. After the air in the reactor was displaced with hydrogen gas toa pressure of 65 kg./cm. stirring and heating was started. Thetemperature of reaction zone rose to 60 C. in five minutes and theabsorption of hydrogen gas stopped in twenty minutes. The reactor wascooled after ten minutes of additional stirring.

The reaction mixture was filtered to remove the catalyst and thefiltrate was evaporated in vacuo at a temperature lower than 60 C. Afteradding a small amount of aqueous sodium hydroxide, the filtrate wasdried up. To the residue were added 150 ml. of water and 50 ml. of

3 concd. aqueous HCl, warmed at a temperature of 70 -80 C. to convertthe glutamic acid into HCl-salt, treated with activated carbon,filtered, transferred into a 500 ml. volumetric cylinder and made up to500 ml. with water.

4 Example 3 In a 500 ml. autoclave, equipped with a vertical magneticstirrer, were placed 62.5 ml. of 28% aqueous ammonia and 3 g. ofpalladium-black catalyst. Hydrogenatknand assa edb $31;fi ggg gi igg ggPgfii i y y 'tion was carried out in the hydrogen gas at a pressure ofThe above reactionwas Inn with five 250 ml portions 3 kg./cm. and ordnary temperature. Aqueous solution 'of the solution, each of which wasallowed to stand for of 'ketoglutanc acld (90 y was Introduced atpredetermined period of time and assayed for the content a rate: of 038acld/mm- Y a Pump over of a-ketoglutaric acid just before thehydrogenation, by a Penocl of p the cohcelljffatlqll 0f the 1111- theamount of precipitate obtained by mixing 4 ml. of the Changed mateflalat about 07% y Welght 111 the Course lutio d 300 1, of 3 0,01 N aqueous2,4-di i1 of the reaction. The reaction mixture was treated asdephenylhydrazine solution. The result of five runs of the scribed inthe preceeding examples; the glutamic acid reaction was shown in thefollowing table. was assayed by Pope and Stevens method and crystalsYield of glutamic acid Content of the unchanged a- Standing Tempera-Period for Initial ketoglutaric period of the ture of hydrogen pressureof acid before a-ketoglutaric reaction gas absorphydrogen the reacacidsolution 0.) tion (min) gas (kgJ (G.) (Percent) tionmper- (hour) cm!)cent ratio to the initial content 0.25 605:5 65 18.8 93. 5 94. 5 0.560i5 20 65 17. s 88. 6 as. 0 1 6015 20 65 15. 2 75. 7 73. 2 2 60i5 20 6513. 9 69. 2 63.6 4 605:5 20 65 12. 7 63. 4 54. s

The result shows the content of a-ketoglutaric acid in were obtained byadjusting pH at 3.2. The yield: 22.0 g. the starting solution and theyield of glutamic acid there- (95.0%). from decreased along with thestanding period of the Example 4 l t 'd l to V ketog u anc am so u 1 nIn a 500 ml. autoclave, equipped with a vertical mag- Example 2 neticstirrer, were placed 250 ml. of alcohol added With In a 500 ml.autoclave, equipped with a vertical magg; 3 2 Platlnum Catalyst Thehydrogena- -netic stirrer, were placed 62.5 ml. of 28% aqueous am- I non3 earned out 111 a y h g P e 01 3 kg/Cm. .monia and f Raneymickelcatalyst After the at ordmary'temperature. Diethyl a-ketoglutarate (24.2

-air in the reactor was displaced with hydrogen gas to a pressure of 30kg./cm. the reaction mixture was stirred and heated to a temperature of60 C. After the constant temperature having been assured, 87.5 ml. of34.3% aqueous solution of disodium m-ketoglutarate was intro- .ducedcontinuously by a pump over a period of 60 min; at a rate of 0.5 g./min.so that the concentration of unchanged OL-kClOgIUtZIlC acid in thereaction mixture was kept at about 0.89%. Absorption of hydrogen ceasedsoon after all the material had been added.

The reaction mixture was filtered to remove the catalyst; the filtratewas evaporated in vacuo at a temperature lower than 60 C. After adding asmall amount of aqueous sodium hydroxide, the filtrate was dried upcompletely. To the residue were added 150 ml. of water and '50 ml.concd. HCl, kept at a temperature of IO-80 C. for converting theglutamic acid into HCl-salt, treated with activated carbon, filtered andtransferred into a 500 ml. volumetric cylinder to be filled up to 500ml. An aliquot g.) was added continuously at a rate of 0.4 g./min. so asto keep the concentration in the reaction mixture lower than 0.4%. Inthe course of the reaction, hydrogen gas was introduced five times intothe reactor. The reaction mixture thus obtained was treated as describedin the of 2 ml. was pipetted out for determining glutamic acid by Popeand Stevens method.

The remaining solution was adjusted at pH 3.2 to crystallize glutamicacid. The following table shows the nearly theoretical yield forglutamic acid obtained b this procedure.

preceeding examples; yield of glutamic acid, 13.7 g. (93.5%

. Intermittent affording ammonia, hydrogen gas and diethyl-a-ketoglutarate into the reactor in the course of the reaction mayyield further amount of a solution containing glutamic acid at a highconcentration.

Example 5 In a 500 ml. autoclave, equipped with a vertical magneticstirrer, were mixed ml. of 28% aqueous ammonia, 3 g. of Raney nickel and16.5 ml. of 34.3% aqueous solution of disodium rx-ketoglutarate to givean aqueous ammonia containing 4% by weight of disodium a-ketoglutarate.The air in the reactor was displaced with hydrogen gas to a pressure of60 kg./cm.'-; the reaction zone was heated to a temperature of 60 C.After the constant temperature having been assured, 158.5 ml. of the34.3% solution of disodium a-ketoglutarate Was introduced into thereactor continuously over 32 min; the rate of addition being regulatedso as to keep the concentra- V Max. con- Yield of glutamic acid Icentration Total amount of of a-keto- Period for Total -ketoglutaricglutaric adding all Reaction Initial volume of Final con- Final conacidintroduced acid in the the a-ketotemperature hydrogen reactioncentration centration m the reaction reaction glutar ic 0.) pressuremixture of glutamic of ammonia (G.) (Percent) zone (g.) mixture in acid(1 m.) (kgJcm?) (ml.) acid (percent) v the course 7 (percent) ofreaction (percent) 7 tion of the unchanged disodium a-ketoglutarate inthe reaction mixture at about 4%, based on the consuming rate ofot-ketoglutaric acid as calculated from dropping rate of hydrogenpressure.

After hydrogen absorption stopped, the content of the reactor wastreated and assayed for glutarnic acid content as described in the aboveexamples. Yield of glutamic acid: 41.2 g. (88.3%).

We claim:

1. A process for the production of a member of the group consisting ofD,L-glutamic acid, lower allryl esters thereof and salts thereof bycatalytic aminative hydrogenation which comprises continuouslyintroducting a starting material selected from the group consisting ofacketoglutaric acid, lower alkyl esters of a-ketoglutaric acid and saltsof a-ketoglutaric acid respectively, to a reaction medium selected fromthe group consisting of an ammonia solution in Water and an ammoniasolution in an alkanol having up to four carbon atoms, at a temperatureof the order of C. to 150 C. in the presence of a hydrogenatingcatalyst, and in a hydrogen atmosphere at a pressure of about 1-200kg./cm. wherein said starting material is introduced at such a rate tosaid reaction medium as to keep the concentration of unchanged startingmaterial calculated as free acid in the reaction mixture, not to exceed2% by weight.

2. A process according to claim 1, wherein said starting material isdissolved in a solvent selected from the group consisting of water andalkanols having up to four carbon atoms.

3. A process for the production of D,L-glumatic acid by catalyticaminative hydrogenation comprising continuously introducinga-ketoglutaric acid to a reaction medium selected from the groupconsisting of an ammonia solution in water and an ammonia solution in analkanol having up to four carbon atoms, at a temperature of the order of10 C. to 150 C. in the presence of a hydrogenating catalyst, and in ahydrogen atmosphere at a pressure of about 1200 kg./cm. wherein saidstarting material is introduced at such a rate to said reaction mediumas to keep the concentration of unchanged starting material calculatedas free acid in the reaction mixture not to exceed 2% by Weight.

4. A process for the production of a salt of glutamic acid by catalyticaminative hydrogenation which comprises continuously introducting a saltof a-ketoglutaric acid to a reaction medium selected from the group ofan ammonia solution in Water and an ammonia solution in an alkanolhaving up to four carbon atoms, at a temperature of the order of 10 C.to 150 C., in the presence of a hydrogenating catalyst, and in ahydrogen atmosphere at a pressure of about 1-200 kg./cm. wherein saidstart- 0 ing material is introduced at such a rate to said reactionmedium as to keep the concentration of unchanged start ing materialcalculated as free acid in the reaction mixture, not to exceed 2% byweight.

5. A process for the production of the disodium salt D,L-glutamic acidby catalytic aminative hydrogenation which comprises continuouslyintroducting an aqueous solution of disodium a-ketoglutarate to areaction medium selected from the group consisting of an ammoniasolution in Water and an ammonia solution in an alkanol having up tofour carbon atoms, at a temperature of the order of 10 C. to C. in thepresence of a hydrogenating catalyst, and in a hydrogen atmosphere at apressure of about 1-200 kg./cm. wherein said starting material isintroduced at such a rate to said reaction medium as to keep theconcentration of unchanged starting material calculated as free acid inthe reaction mixture not to exceed 2% by weight.

6. A process for the production of a lower alkyl ester of glutarnic acidby catalytic aminative hydrogenation which comprises continuouslyintroducting a lower alkyl ester of a-ketoglutaric acid to a reactionmedium selected from the group consisting of an ammonia solution inwater and an ammonia solution in an alkanol having up to four carbonatoms, at a temperature of the order of 10 C. to 150 C., in the presenceof a hydrogenating catalyst, and in a hydrogen atmosphere at a pressureof about 1200 kg./cm. wherein said starting material is introduced atsuch a rate to said reaction medium as to keep the concentration ofunchanged starting material calculated as free acid in the reactionmixture, not to exceed 2% by weight.

7. A process for the production of the diethyl ester of D,L-glutamicacid by catalytic aminative hydrogenation which comprises continuouslyintroducing diethyl a-ketoglutarate to a reaction medium selected fromthe group consisting of an ammonia solution in water and an ammoniasolution in an alkanol having up to four carbon atoms, at a temperatureof the order of 10 C. to 150 C. in the presence of a hydrogenatingcatalyst, and in a hydrogen atmosphere at a pressure of about 1-200kg./cm. wherein said starting material is introduced at such a rate tosaid reaction medium as to keep the concentration of unchanged startingmaterial calculated as free acid in the reaction mixture not to exceed2% by weight.

References Cited in the file of this patent UNITED STATES PATENTS2,610,212 Floyd Sept. 9, 1952

1. A PROCESS FOR THE PRODUCTION OF A MEMBER OF THE GROUP CONSISTING OFD,L-GLUTAMIC ACID, LOWER ALKYL ESTERS THEREOF AND SALTS THEREOF BYCATALYTIC AMINATIVE HYDROGENATION WHICH COMPRISES CONTINUOUSLYINTRODUCING A STARTING MATERIAL SELECTED FROM THE GROUP CONSISTING OFAKETOGLUTARIC ACID, LOWER ALKYL ESTERS OF A-KETOGLUTARIC ACID AND SALTSOF A-KETOGLUTARIC ACID RESPECTIVELY, TO A REACTION MEDIUM SELECTED FROMTHE GROUP CONSISTING OF AN AMMONIA SOLUTION IN WATER AND AN AMMONIASOLUTION IN AN ALKANOL HAVING UP TO FOUR CARBON ATOMS, AT A TEMPERATUREOF THE ORDER OF 10*C. TO 150*C. IN THE PRESENCE OF A HYDROGENATINGCATALYST, AND IN A HYDROGEN ATMOSPHERE AT A PRESSURE OF ABOUT 1-200KG./CM.2, WHEREIN SAID STARTING MATERIAL IS INTRODUCED AT SUCH A RATE TOSAID REACTION MEDIUM AS TO KEEP THE CONCENTRATION OF UNCHANGED STARTINGMATERIAL CALCULATED AS FREE ACID IN THE REACTION MIXTURE, NOT TO EXCEED2% BY WEIGHT.